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Ortiz-Cordero C, Bincoletto C, Dhoke NR, et al. Defective autophagy and increased apoptosis contribute toward the pathogenesis of FKRP-associated muscular dystrophies. Stem Cell Reports. 2021;16(11):2752-2767doi: 10.1016/j.stemcr.2021.09.009.
Ortiz-Cordero, C., Bincoletto, C., Dhoke, N. R., Selvaraj, S., Magli, A., Zhou, H., Kim, D. H., Bang, A. G., & Perlingeiro, R. C. R. (2021). Defective autophagy and increased apoptosis contribute toward the pathogenesis of FKRP-associated muscular dystrophies. Stem cell reports, 16(11), 2752-2767. https://doi.org/10.1016/j.stemcr.2021.09.009
Ortiz-Cordero, Carolina, et al. "Defective autophagy and increased apoptosis contribute toward the pathogenesis of FKRP-associated muscular dystrophies." Stem cell reports vol. 16,11 (2021): 2752-2767. doi: https://doi.org/10.1016/j.stemcr.2021.09.009
Ortiz-Cordero C, Bincoletto C, Dhoke NR, Selvaraj S, Magli A, Zhou H, Kim DH, Bang AG, Perlingeiro RCR. Defective autophagy and increased apoptosis contribute toward the pathogenesis of FKRP-associated muscular dystrophies. Stem Cell Reports. 2021 Nov 09;16(11):2752-2767. doi: 10.1016/j.stemcr.2021.09.009. Epub 2021 Oct 14. PMID: 34653404; PMCID: PMC8581053.
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Stem Cell Reports. 2021 Nov 09;16(11):2752-2767. doi: 10.1016/j.stemcr.2021.09.009. Epub 2021 Oct 14.

Defective autophagy and increased apoptosis contribute toward the pathogenesis of FKRP-associated muscular dystrophies.

Stem cell reports

Carolina Ortiz-Cordero, Claudia Bincoletto, Neha R Dhoke, Sridhar Selvaraj, Alessandro Magli, Haowen Zhou, Do-Hyung Kim, Anne G Bang, Rita C R Perlingeiro

Affiliations

  1. Lillehei Heart Institute, Department of Medicine, University of Minnesota, 4-128 CCRB, 2231 6th St. SE, Minneapolis, MN 55455, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA.
  2. Lillehei Heart Institute, Department of Medicine, University of Minnesota, 4-128 CCRB, 2231 6th St. SE, Minneapolis, MN 55455, USA; Departamento de Farmacologia, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.
  3. Lillehei Heart Institute, Department of Medicine, University of Minnesota, 4-128 CCRB, 2231 6th St. SE, Minneapolis, MN 55455, USA.
  4. Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  5. Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
  6. Lillehei Heart Institute, Department of Medicine, University of Minnesota, 4-128 CCRB, 2231 6th St. SE, Minneapolis, MN 55455, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA. Electronic address: [email protected].

PMID: 34653404 PMCID: PMC8581053 DOI: 10.1016/j.stemcr.2021.09.009

Abstract

Fukutin-related protein (FKRP) is a glycosyltransferase involved in glycosylation of alpha-dystroglycan (α-DG). Mutations in FKRP are associated with muscular dystrophies (MD) ranging from limb-girdle LGMDR9 to Walker-Warburg Syndrome (WWS), a severe type of congenital MD. Although hypoglycosylation of α-DG is the main hallmark of this group of diseases, a full understanding of the underlying pathophysiology is still missing. Here, we investigated molecular mechanisms impaired by FKRP mutations in pluripotent stem (PS) cell-derived myotubes. FKRP-deficient myotubes show transcriptome alterations in genes involved in extracellular matrix receptor interactions, calcium signaling, PI3K-Akt pathway, and lysosomal function. Accordingly, using a panel of patient-specific LGMDR9 and WWS induced PS cell-derived myotubes, we found a significant reduction in the autophagy-lysosome pathway for both disease phenotypes. In addition, we show that WWS myotubes display decreased ERK1/2 activity and increased apoptosis, which were restored in gene edited myotubes. Our results suggest the autophagy-lysosome pathway and apoptosis may contribute to the FKRP-associated MD pathogenesis.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords: dystroglycanopathies; iPS cells; in vitro modeling; skeletal muscle

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